Syntheses of all conformationally locked northern and southern nucleosides (a total of eight different target compounds) on a bicyclo[3.1.0]hexane template with the four common bases were developed. New synthetic methodologies are still being explored to secure enough quantities of these compounds. A newly developed approach allowed us to make both 4',6'-cyclopropane-fused (northern) and 1',6'-cyclopropane-fused (southern) carbocyclic nucleosides from the same homochiral precursor, (1S,2R)-2-[(benzyloxy)methyl]cyclopent-3-enol. A conformational analysis of these compounds (MM2 parameters) showed that the northern conformers prefer an anti glycosyl torsion angle, whereas the southern ones exist preferentially in the syn range. The compounds were tested against a variety of viruses and activity was mostly associated with the northern conformers, except for the adenosine southern conformer which was active against HCMV. Activity against herpes viruses was excellent, and the potency of the northern thymidine analogue surpassed that of acyclovir. At the macromolecular level, with the synthesis of oligonucleotides containing these rigid conformers, we envision the following applications: 1) synthesis of antisense oligonucleotides, particularly for construction of "gapmers" since each rigid thymidine increases the Tm of DNA/RNA duplexes by 1.3 degrees C, 2) synthesis of oligonucleotides containing enforced helical structures with a bend through appropriate combinations of rigid pseudonucleosides, and 3) synthesis of ribozymes where the substitution of ribonucleosides by 2'-deoxycarba-ribonucleosides can be performed without losing the 3'-endo co conformation.